Integrins are α or β heterodimeric cell surface receptors which bind to extracellular matrix adhesive proteins such as fibrinogen, fibronectin, vitronectin, and osteopontin. These transmembrane glycoproteins (GP's), known for their large extracellular domains, are classified by the β subunit. The β3 class of the integrin family has received the most attention in recent drug discovery efforts (W. J. Hoekstra, Current Medicinal Chemistry, 1998, 5, 195). Some of the disease states that have a strong β3 integrin component in their etiologies are thrombosis (integrin α2bβ3, also called GPIIb/IIIa), unstable angina (GPIIb/IIIa), restenosis (GPIIb/IIIa and integrin αvβ3), osteoporosis (αvβ3) and tumor metastasis (αvβ3). Antibodies and/or low-molecular weight compound antagonists of αvβ3 have shown efficacy against these respective disease states in animal models (J. Samanen, Current Pharmaceutical Design, 1997, 3, 545–584) and, thereby, offer promise as medicinal agents.
Antagonists of GPIIb/IIIa and αvβ3 have typically been designed after the bioactive arginine-glycine-aspartate (RGD) conformations of peptides derived from their primary ligands, fibrinogen and vitronectin, respectively. The RGD motif is the general cell attachment sequence of many extracellular matrices, blood and cell surface proteins, as half of approximately 20 known integrins bind the RGD-containing adhesion ligands. To discover RGD peptides with integrin selectivity, peptides with both restricted conformations and alterations of flanking residues have been studied. Iterative synthesis and computer modelling of these cyclic and alicyclic peptides have provided potent, selective agents as a platform for nonpeptide GPIIb/IIIa or αvβ3 antagonist design.
PCT Application WO 99/50249 describes guanidine-like compounds, unlike those of the present invention, as antagonists of αvβ3 and α2bβ3 integrin and related cell surface adhesive protein receptors.
PCT Application WO 01/10867 describes the use of benzazepine ethers and other compounds, unlike those of the present invention, as vitronectin antagonists for treating stroke and the post-traumatic injury associated with stroke.
Accordingly, it is an object of the present invention to provide quinazoline and quinazoline-like compounds that are integrin antagonists. It is an object of the invention to provide quinazoline and quinazoline-like compounds that are αvβ3, αvβ5, αvβ6 and GPIIb/IIIa integrin antagonists. It is also an object to provide a method for using a compound of the present invention for treating integrin-mediated disorders.